Method and device for enhanced composition delivery

ABSTRACT

Methods and devices that provide enhanced delivery of a composition to a body region of a patient utilizing radiofrequency energy include directing a first electrode and a second electrode coupled to a radiofrequency energy source to a location proximate to the body region. Radiofrequency energy is provided in modulated pulses from the radiofrequency energy source to the body region from at least one of the first electrode and the second electrode to provide a delivery condition configured to enhance delivery of the composition. The composition is delivered proximate to the body region using a composition delivery element. Devices for enhance composition delivery are also disclosed.

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/410,685, filed on Oct. 20, 2016, which is herebyincorporated by reference in its entirety.

FIELD

The present invention relates to a method and device for enhancedcomposition delivery.

BACKGROUND

Current methods and devices for treating occlusions in the body (bloodvessel or grafts) employ the use of balloon catheters or stents todeliver drugs to the inside of the blood vessel. Drug eluting stentsprovide the advantage that the device can be designed to prolongdelivery of the drug for several weeks or several months by altering thedrugs elution profile, but in most cases leave behind a metallicscaffold. Drug coated balloons provide the advantage of not leavinganything behind, however the drug is delivered for a shorter period oftime due to the fact that the vessel is occluded by the balloon whilethe drug is being delivered.

In both devices, the primary mechanism of delivery is simple diffusionof the drug into the vessel wall and is subject to washout of the drugwhile under flow conditions. Moreover, since simple diffusion is theprimary mechanism of delivery, in both devices the drug is deliveredsuperficially onto the vessel wall.

SUMMARY

A method for enhanced delivery of a composition to a body region of apatient utilizing radiofrequency energy includes directing a firstelectrode and a second electrode coupled to a radiofrequency energysource to a location proximate to the body region. Radiofrequency energyis provided in modulated pulses from the radiofrequency energy source tothe body region from at least one of the first electrode and the secondelectrode to provide a delivery condition configured to enhance deliveryof the composition. The composition is delivered proximate to the bodyregion using a composition delivery element.

A device for enhanced delivery of a composition to a body region of apatient utilizing radiofrequency energy includes a first longitudinalmember with a proximal end and a distal end with at least one lumenextending between the proximal end and the distal end. A compositiondelivery element is located at the distal end of the longitudinalmember. The composition delivery element has the composition coated onan outside surface thereof. At least two electrodes are coupled to aradiofrequency source and located within the composition deliveryelement. The electrodes are insulated such that at least two electrodesare capable of generating an electric field to enhance delivery of thecomposition to the body region.

This technology provides a number of advantages including providing moreefficient and effective devices and methods for delivering a compositionto a body region. The devices and methods of this technology allow thecomposition to remain within the body region site for an extended periodof time to provide enhanced treatment. In particular, the use ofcavitation, shockwaves, electroporation, or the like, generated byradiofrequency energy or other energy source aids in the delivery of thecomposition. The present technology advantageously provides an enhancedmethod for delivering the drug into the vessel wall or occlusion suchthat the drug remains within the targeted site for a longer period oftime without leaving anything behind. Prolonged action of the drugwithin the targeted site can lead to improved outcomes (e.g. reducedreocclusion, restenosis, or revascularization rates).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of an exemplary device for composition deliveryusing radiofrequency energy of the present technology.

FIG. 2 is a schematic of another exemplary device for compositiondelivery using radiofrequency energy of the present technology locatedin a body region having an occlusion.

FIG. 3 is a schematic of a further exemplary device for compositiondelivery using radiofrequency energy of the present technology locatedin a body region having an occlusion.

FIG. 4 is a schematic of an alternative example of the device forcomposition delivery shown in FIG. 3.

FIG. 5 is a schematic of the exemplary device for composition deliveryusing radiofrequency energy shown in FIG. 1 illustrating an exemplarycoupling between the electrodes and the radiofrequency energy source.

FIG. 6 is a schematic end view of the longitudinal member of FIG. 5 withtwo coupled, insulated electrodes.

FIG. 7 is a schematic of an exemplary device for composition deliverywith another exemplary composition delivery element.

FIG. 8 is a schematic of a configuration for securing an exemplaryraised element to an exemplary composition delivery element that may beemployed with the composition delivery device of the present technology.

FIGS. 9A-9C illustrates an exemplary method for enhanced compositiondelivery using radiofrequency energy.

FIG. 10 illustrates a schematic of another exemplary compositiondelivery device with a composition delivery element with a poroussurface.

FIG. 11 illustrates the effect of plasma-mediated ablation usingradiofrequency energy within a nonoccluded vessel.

DETAILED DESCRIPTION

An exemplary composition delivery device 10 for enhanced delivery of acomposition to a body region of a patient utilizing radiofrequencyenergy is illustrated in FIGS. 1 and 5. Although radiofrequency energyis described, other energy modalities, such as ultrasound or laserenergy by way of example, may be utilized. The composition deliverydevice 10 includes a first longitudinal member 12 including electrodes14(1) and 14(2), a radiofrequency energy source 16, and a compositiondelivery element 18, although the composition delivery device 10 couldinclude other types and/or numbers of elements, components, and/ordevices in other configurations, such as additional electrodes and/orlongitudinal members. This exemplary technology provides a number ofadvantages including providing more efficient and effective compositiondelivery to a region within the body of a patient.

Referring more specifically to FIG. 1, the composition delivery device10 includes a first longitudinal member 12 that is configured to beadvanced into the body of a patient and located near a body region ofthe patient. The body region may be various regions in the body,including organs, body lumens or cavities, such as various ducts orvessels, blood vessels, grafts, glands. In one example, the body regionmay be an area in the body including an occlusion or a tumor thatrequires treatment. In this example, the first longitudinal member 12includes a lumen 19 extending between a proximal end 20 and a distal end22 of the first longitudinal member 12, although the longitudinal member12 may include additional lumens. The lumen 19 is configured to receiveadditional longitudinal members therein, such as guidewires, catheters,microcatheters, or probes, by way of example only.

In this example, the longitudinal member 12 has electrodes 14(1) and14(2) located thereon to provide a bipolar arrangement of the electrodes14(1) and 14(2), although the electrodes 14(1) and 14(2) may be locatedon other elements in other configurations to provide a bipolararrangement.

In another example, as shown in FIG. 2, the composition delivery device10 further includes a second longitudinal member 13 that is configuredto be inserted into the lumen 19 of the first longitudinal member 12 tobe delivered proximate to the body region of the patient. In thisexample, the second longitudinal member 13 is a guidewire or a catheterwith the electrodes 14(1) and 14(2) located thereon to provide thebipolar arrangement.

In yet another example, as shown in FIG. 3, the composition deliverydevice 10 further includes a third longitudinal member 23 that isconfigured to be inserted into the lumen 19 of the first longitudinalmember. The third longitudinal member 23 may be a guidewire or acatheter, by way of example only. The second longitudinal member 13 andthe third longitudinal member 23, which are independent, non-overlappingguidewires or catheters, may be delivered to the body region in the samedirection or in opposition directions as described below.

In a further example, one of the electrodes 14(1) or 14(2) is located ona patch that may be placed on the patient's skin proximate the bodyregion of the patient to be treated. The patch is placed in closeproximity to the body region to allow for the bipolar arrangementbetween the electrodes 14(1) and 14(2).

Referring now to FIG. 4, in one example the lumen 19 of the firstlongitudinal member 12 includes multiple lumen sections to deliver thesecond longitudinal member 13 and the third longitudinal member 23separately to the body region. In yet another example, the secondlongitudinal member 13 may be configured to receive the thirdlongitudinal member 23 such that the third longitudinal member 23 islocated within the second longitudinal member 13. Referring again toFIG. 3, in this example the electrodes 14(1) and 14(2) are located onthe second longitudinal member 13 and the third longitudinal member 23,respectively, in order to provide the bipolar arrangement.

In one example, the electrodes 14(1) and 14(2) may be balloon markers,although other types of electrodes may be utilized. Referring to FIG. 5,the electrodes 14(1) and 14(2) are coupled to the radiofrequency energysource 16 via wires 17(1) and 17(2). The wires 17(1) and 17(2) arewrapped in a helical configuration about the first longitudinal member12. The wires 17(1) and 17(2) deliver radiofrequency energy from theradiofrequency energy source 16 to provide radiofrequency energy to thebody region, although other energy sources configured to supply otherenergy modalities may be employed.

Referring now to FIG. 6, the electrodes 14(1) and 14(2) are insulated,such as with a dielectric barrier, such that the two electrodes 14(1)and 14(2) are capable of generating an electric field in the bodyregion. Further, the insulation is selected to allow the electrodes14(1) and 14(2) to be capable of withstanding the generation of a plasmadischarge around the electrodes 14(1) and 14(2). The electrodes 14(1)and 14(2) may further have a dielectric barrier located at an exposedportion of the electrodes 14(1) and 14(2) to further aid in withstandingplasma generation.

Referring again more specifically to FIGS. 1 and 5, the radiofrequencyenergy source 16 provides a source of radiofrequency energy that isdelivered to the body region through electrodes 14(1) and 14(2),although other energy modalities may be employed. In one example, theradiofrequency energy source 16 provides modulated pulses ofradiofrequency energy to the electrodes 14(1) and 14(2). In one example,the radiofrequency energy source 16 is configured to provide modulatedpulses having a pulse width between about 0.05 to about 500microseconds, although modulated pulses having a pulse width of lessthan 0.05 microseconds or between 500 microseconds and 1 second may beemployed. The radiofrequency energy source 16 may further be configuredto provide the modulated pulses in packets. Each packet of modulatedpulses may have between 2 and 10 pulses, by way of example only. Inanother example, the modulated pulses are grouped into bursts having aburst width between 100 ms to 1 s and an interval between each burstbetween 1 ms to 100 ms, by way of example only.

The radiofrequency energy source 16 provides radiofrequency energy at avoltage between 400V to 4000V, although voltages less than 400V may beutilized in some examples. The radiofrequency energy source 16 iscapable of providing radiofrequency energy at a level that produces adelivery condition in the body region that enhances delivery of thecomposition, such as cavitation, microjets, shockwaves, electricalstimulation, or a chemical reaction. In one example, the radiofrequencyenergy source 16 provides energy to generate shockwaves having aninstantaneous magnitude between 0.1 MPa to 20 MPa. In another example,the radiofrequency energy source 16 provides energy to generate one ormore regions of cavitation bubbles in the body region having a diameterbetween 1 μm and 10 mm. The cavitation bubbles may be formed from thecomposition delivered to the body region using the composition deliverydevice 10.

Referring again to FIGS. 1 and 5 more specifically, the compositiondelivery device 10 further includes the composition delivery element 18located at the distal end 22 of the first longitudinal member 12. Thecomposition delivery element 18 includes a composition layer 24 of thecomposition to be delivered to the body region located on a surface 25of the composition delivery element 18. The composition layer 24 iscoated on and/or imbedded within the surface 25 of the compositiondelivery element 18. Methods of applying the composition layer 24 caninclude spraying, dip coating, vapor deposition, plasma deposition,using a chemical bond, or using an electrical bond, by way of exampleonly.

In another example the composition, rather than being placed on theoutside of the composition delivery element, is injected inside thecomposition delivery element 18. The composition delivery element 18includes pores 50 that allow the composition to escape through the pores50 and be delivered into the body region, such as an occlusion or vesselwall as shown in FIG. 10. This delivery of the composition is enhancedby activation of radiofrequency energy as described further below. Inanother example the composition is located on the composition deliveryelement as a charged compound. The radiofrequency energy is thendelivered with a similar charge so the composition is repelled from thecomposition delivery element 18 and into the tissue. Additionally oralternatively, an electrically neutral therapeutic agent may be modifiedby adding a charged moiety such that the modified therapeutic agentcomprising the charged moiety may be more susceptible to the influenceof the energy field. Additionally, the therapeutic agent may besubmerged or dissolved in a conductive fluid, whereby the conductivefluid path under the influence of the energy field as described aboveserves as a vehicle to facilitate the delivery of the therapeutic agentto the treatment region. By way of example, drugs to treat anemia may beused.

The composition is a therapeutic agent or a pharmaceutical compound.Non-limiting examples of the compositions that may be utilized with thecomposition delivery device include a thrombolytic agent, a fibrinolyticenzyme, a thrombin inhibitor, an antiplatelet agent, an anticoagulant,an anti-restenotic agent, or an anti-cancer agent, although othertherapeutic agents or pharmaceutical compounds may be delivered usingthe composition delivery device 10. The composition can be a drug, gas,or liquid which can have an effect on the targeted body region. As anexample, the composition could be Paclitaxel or a drug taken from thelimus family of drugs and used to be delivered to the vessel body of anocclusion to reduce the likelihood of such vessel from reoccluding orrestenosing.

It is contemplated that the present embodiments may be used to deliverother therapeutic agents or other biologically active substancesincluding but not limited to: amino acids, anabolics, analgesics andantagonists, anesthetics, anthelmintics, anti-adrenergic agents,anti-asthmatics, anti-atherosclerotics, antibacterials,anticholesterolics, anti-coagulants, antidepressants, antidotes,anti-emetics, anti-epileptic drugs, anti-fibrinolytics,anti-inflammatory agents, antihypertensives, antimetabolites,antimigraine agents, antimycotics, antinauseants, antineoplastics,anti-obesity agents, anti-Parkinson agents, antiprotozoals,antipsychotics, antirheumatics, antiseptics, antivertigo agents,antivirals, bacterial vaccines, bioflavonoids, calcium channel blockers,capillary stabilizing agents, coagulants, corticosteroids, detoxifyingagents for cytostatic treatment, contrast agents (like contrast media,radioisotopes, and other diagnostic agents), electrolytes, enzymes,enzyme inhibitors, gangliosides and ganglioside derivatives,hemostatics, hormones, hormone antagonists, hypnotics, immunomodulators,immunostimulants, immunosuppressants, minerals, muscle relaxants,neuromodulators, neurotransmitters and nootropics, osmotic diuretics,parasympatholytics, para-sympathomimetics, peptides, proteins,respiratory stimulants, smooth muscle relaxants, sympatholytics,sympathomimetics, vasodilators, vasoprotectives, vectors for gentherapy,viral vaccines, viruses, vitamins, and the like.

In this example, the composition delivery element 18 is an expandableballoon having a porous surface 25 to which the composition layer 24 isapplied, although other composition delivery elements, such as anexpandable catheter, or a stent may be utilized. In another example, thecomposition delivery element 18 may be microbubbles filled with thecomposition that are delivered to the body region through the lumen 19of the first longitudinal member 12, by way of example. In anotherexample, as shown in FIG. 7, the composition delivery element 18comprises a plurality of expandable ribs with the composition locatedthereon.

Referring now again more specifically to FIGS. 1 and 5, the compositiondelivery element 18, such as a balloon, includes one or more raisedelements 28 located on the surface 25 thereof. The raised elements 28are configured to simultaneously score or cut the body region, such asan occlusion, so that a composition can more readily diffuse into thearea into which the composition delivery element 18 is inserted. Theraised elements 28 may comprise longitudinal or circumferential elementslocated on the composition delivery element 18. In one example, theraised elements 28 have a triangular cross section, although otherconfigurations may be utilized. The raised elements 28 are constructedof a metal or a polymer, by way of example, although other materials maybe utilized. The composition layer 24 may be applied directly to theraised elements 28 of the composition delivery element 18. In thisexample, the raised elements 28 are coupled directly to the compositiondelivery element 12. Alternatively, referring now to FIG. 8, the raisedelements 28 may be coupled directly to the first longitudinal member 12,although other configurations may be utilized.

An example of a method for enhanced delivery of a composition to a bodyregion of a patient utilizing radiofrequency energy will now bedescribed with reference to FIGS. 1-8. First, the longitudinal member 12including the composition delivery element 18 with the composition layer24 located on the surface 25 is delivered to the body region of thepatient to be treated. The body region may be various regions in thebody such as organs, body lumens or cavities, such as various ducts orvessels, blood vessels, grafts, glands. In one example, the body regionmay be an area in the body including an occlusion or a tumor thatrequires treatment. The composition layer 24 may be coated or imbeddedon the surface 25 of the composition delivery element 18, although inother examples the composition layer 24 may be located on the raisedelements protruding from the surface 25 of the composition deliveryelement 18, such as an expandable balloon.

Once located in the body region, the composition delivery element 18 maybe expanded to apply the composition layer 24 to the body region. Thecomposition is a therapeutic agent or a pharmaceutical compound.Non-limiting examples of the compositions that may be utilized with thecomposition delivery device include a thrombolytic agent, a fibrinolyticenzyme, a thrombin inhibitor, an antiplatelet agent, an anticoagulant,an anti-restenotic agent, or an anti-cancer agent, although othertherapeutic agents or pharmaceutical compounds may be delivered usingthe composition delivery device 10.

Next, the first electrode 14(1) and the second electrode 14(2) coupledto the radiofrequency energy source 16 are directed to the locationproximate to the body region. In one example, the longitudinal member 12has electrodes 14(1) and 14(2) located thereon, as shown in FIGS. 1 and5, such that the electrodes 14(1) and 14(2) are delivered simultaneouslywith the longitudinal member 12.

In another example, as shown in FIG. 2, the electrodes 14(1) and 14(2)are delivered on second longitudinal member 13 that is configured to beinserted into the lumen 19 of the first longitudinal member 12 to bedelivered proximate to the body region of the patient. In this example,the electrodes 14(1) and 14(2) are directed to the body region afterdelivery of the composition delivery element 18.

In yet another example, as shown in FIG. 3, the electrodes 14(1) and14(2) are directed separately to the body region through the lumen 19 ofthe first longitudinal member 12 on the second longitudinal member 13and the third longitudinal member 23, which are independent,non-overlapping guidewires or catheters, respectively. In this example,the second longitudinal member 13 and the third longitudinal member 23may be delivered to the body in the same direction or in oppositiondirections, using an antegrade/retrograde approach, as described in U.S.Pat. No. 9,561,073, the disclosure of which is incorporated herein byreference in its entirety.

As disclosed in U.S. Pat. No. 7,918,859 by the same inventors, which isincorporated herein in its entirety, in the controlled antegrade andretrograde tracking (CART) technique the retrograde approach takesadvantage of an intercoronary channel. Such a channel may be anepicardial channel, an inter-atrial channel, an intra-septal channel(also referred to as septal collateral), or a bypass graft. The basicconcept of the CART technique is to create a channel through anocclusion, preferably with limited dissections, by approaching theocclusion both antegradely and retrogradely.

In a further example, a patch including one of the electrodes 14(1) or14(2) is placed on the patient's skin proximate the body region of thepatient to be treated. The patch is placed in close proximity to thebody region to allow for the bipolar arrangement between the electrodes14(1) and 14(2).

Next, radiofrequency energy is delivered from the radiofrequency energysource 16 to the electrodes 14(1) and 14(2) in modulated pulses. In oneexample, the radiofrequency energy source 16 provides modulated pulseshaving a pulse width between about 0.05 to about 500 microseconds,although modulated pulses having a pulse width of less than 0.05microseconds or between 500 microseconds and 1 second may be employed.The radiofrequency energy source 16 may further provide the modulatedpulses in packets having between 2 and 10 pulses, by way of exampleonly. In another example, the modulated pulses are grouped into burstshaving a burst width between 100 ms to 1 s and an interval between eachburst between 1 ms to 100 ms, by way of example only.

The delivery of the modulated pulses may be gated using anelectrocardiogram (ECG) or another waveform signal obtained from thebody of the patient. In one example, a third patch containing anelectrode may be placed outside of the body region and electricallycoupled to the electrodes 14(1) and 14(2). In yet another example, athird electrode may be located near the body region in order measureimpedance based on the delivery of the radio frequency energy. Theimpedance measurements may then be utilized to optimize the delivery ofthe radiofrequency energy.

The radiofrequency energy source 16 provides the radiofrequency energyat a voltage between 400V to 4000V, although voltages less than 400V maybe utilized in some examples. In one example, the incident intensity ofthe radiofrequency energy in the body region is between about 0.1 Joulesto 5 Joules per square millimeter. In one example, the radiofrequencyenergy is delivered until an electrical limit, such as 100 Ohms, is met,although other electrical limits may be employed.

The radiofrequency energy source 16 provides radiofrequency energy at alevel that produces a delivery condition in the body region thatenhances delivery of the composition, such as cavitation, microjets,shockwaves, electrical stimulation, or a chemical reaction. In oneexample, the radiofrequency energy source 16 provides energy to generateshockwaves having an instantaneous magnitude between 0.1 MPa to 20 MPa.In another example, the radiofrequency energy source 16 provides energyto generate one or more regions of cavitation bubbles in the body regionhaving a diameter between 1 μm and 10 mm. The cavitation bubbles may beformed from the composition delivered to the body region using thecomposition delivery device 10.

The delivery of radiofrequency energy provides for prolonged delivery ofthe composition and imbedding of the composition within the body regionto provide enhanced treatment. The radiofrequency signal can be adjustedusing a number of modifications to the pulse such as by shortening orlengthening the pulse duration or adjusting the pulse period. As anexample, by shortening the pulse duration to the micro or nanosecondrange, a stronger mechanical effect can be obtained inducing strongermechanical effects (i.e. deeper injection or imbedding) of thecomposition into the body region. A deeper imbedding of the compositionis likely to result in a longer duration of the composition within thebody region enabling a more durable effect from the composition.

By way of example, the delivery of radiofrequency energy may be utilizedto provide a mechanical force that enhances diffusion of the compositioninto the body region. Alternatively, the radiofrequency energy may beemployed to cause impacts on the body region itself, such asvasodilation, increased cell permeability, or reversible electroporationthat increase the effectiveness of the delivery of the composition tothe body region.

By way of example, the method may be utilized to treat on occlusion. Theradiofrequency energy is applied between the two electrodes 14(1) and14(2) generating a plasma and modifying the surrounding plaque orocclusion or vessel wall utilizing the effects of the plasma generation,such as cavitation or shockwaves. The composition is delivered to theocclusion, which has now become more amenable to diffusion or deliveryof the composition due to the effects of the plasma generation, thusenhancing the delivery of the composition into the vessel wall. Thedelivery of the radiofrequency energy to the vessel wall or occlusioncan induce vasodilation, alter cell permeability, or electroporation orthe like to enhance the delivery of the composition. By adjusting theradiofrequency signal, the composition can be delivered deeper into thevessel wall, thus allowing the composition to remain within the vesselwall for a prolonged period of time and improving the durability of thecomposition within the vasculature.

In another example, the electrodes 14(1) and 14(2) are placed on thesame device as the composition, which allows for simultaneousmodification of the surrounding tissue and delivery of radiofrequencyenergy to enhance delivery of the composition. In this example, thecomposition delivery element 18, such as a balloon catheter, has thecomposition layer 24 placed on the outside surface 25 of the balloon.The electrodes 14(1) and 14(2) are located inside the compositiondelivery element 18 as either an attachment to the first longitudinalmember 12 as shown in FIG. 1, or delivered through the lumen 19 of thefirst longitudinal member 12 as shown in FIGS. 2 and 3. Theradiofrequency energy is then delivered and the effects of theradiofrequency energy are transmitted through the composition deliveryelement 18, such as a balloon, to the composition layer 24 and thevessel wall enhancing delivery of the composition to the vessel wall.

Another exemplary method for enhanced delivery of a composition to abody region of a patient, such as an occlusion, utilizing radiofrequencyenergy will now be described with reference to FIGS. 9A-9C. In thisexample, electrodes 14(1) and 14(2) are directed to the occluded area inthe vessel on the second longitudinal member 13 and the thirdlongitudinal member 23 prior to delivery of the composition to the bodyarea, as shown in FIG. 9A.

Radiofrequency energy is then applied as set forth above. Theapplication of radiofrequency energy generates a plasma and modifies thesurrounding plaque or occlusion or vessel wall utilizing the effects ofthe plasma generation, such as cavitation or shockwaves, as shown inFIG. 9B. The electrodes 14(1) and 14(2) are then removed from the bodyregion.

Next, the composition is delivered to the occlusion using compositiondelivery element 18 as shown in FIG. 9C. The occlusion has become moreamenable to diffusion or delivery of the composition due to the effectsof the plasma generation, thus enhancing the delivery of the compositioninto the vessel wall. The delivery of the radiofrequency energy to thevessel wall or occlusion can induce vasodilation, alter cellpermeability, or electroporation or the like to enhance the delivery ofthe composition. By adjusting the radiofrequency signal, the compositioncan be delivered deeper into the vessel wall, thus allowing thecomposition to remain within the vessel wall for a prolonged period oftime and improving the durability of the composition within thevasculature.

EXAMPLE

Preclinical work (FIG. 11) has shown that at very high voltages, theeffect of plasma-mediated ablation using radiofrequency energy within anonoccluded vessel can result in effects that propagate into the vesselwall. In particular, medial dissections and/or hemorrhagingperivascularly can occur into the outer vessel wall. However, byaltering the radiofrequency delivery settings, these effects can becontrolled such that they enhance delivery of a composition into thevessel wall or occlusion without creating deleterious effects. Examplesof alterations can include reducing the voltage or current levels,modifying the pulse period, modifying the pulse duration, or modifyingthe number of pulses delivered during radiofrequency delivery.

As an example, in the case of an occlusion in a vessel wall, it has beenshown that the use of voltages in the range of 1200V to 2000V can ablatetissue and create a channel through the occlusion in a very short periodof time. The delivery of drugs or other compositions would likelyrequire less energy or a lower voltage as the objective is not to createa channel but to enhance the delivery of the drug into the vessel wall.Similarly, it has been shown that very short pulses (on the order ofnano seconds) generally create larger mechanical forces (e.g.shockwaves) than longer pulses. It would be preferred to deliver enoughmechanical force to enhance delivery of the drug or composition into thevessel wall without causing damage to the wall itself.

Accordingly, as illustrated and described by way of the examples hereinthis technology provides more efficient and effective devices andmethods for delivering a composition to a body region. The devices andmethods of this technology allow the composition to remain within thebody region site for an extended period of time to provide enhancedtreatment. In particular, the use of cavitation, shockwaves,electroporation, or the like, generated by radiofrequency energy orother energy source aids in the delivery of the composition. Thistechnology also advantageously provides an enhanced method fordelivering a drug into a vessel wall or occlusion such that the drugremains within the targeted site for a longer period of time withoutleaving anything behind. Prolonged action of the drug within thetargeted site can lead to improved outcomes (e.g. reduced reocclusion,restenosis, or revascularization rates)

Having thus described the basic concept of the invention, it will berather apparent to those skilled in the art that the foregoing detaileddisclosure is intended to be presented by way of example only, and isnot limiting. Various alterations, improvements, and modifications willoccur and are intended to those skilled in the art, though not expresslystated herein. These alterations, improvements, and modifications areintended to be suggested hereby, and are within the spirit and scope ofthe invention. Accordingly, the invention is limited only by thefollowing claims and equivalents thereto.

What is claimed is:
 1. A method for enhanced delivery of a compositionto a body region of a patient utilizing radiofrequency energy, themethod comprising: directing a first electrode and a second electrodecoupled to a radiofrequency energy source to a location proximate to thebody region; providing radiofrequency energy in modulated pulses fromthe radiofrequency energy source to the body region from at least one ofthe first electrode and the second electrode to provide a deliverycondition configured to enhance delivery of the composition; anddelivering the composition proximate to the body region using acomposition delivery element.
 2. The method of claim 1, wherein thecomposition is a therapeutic agent or a pharmaceutical compound.
 3. Themethod of claim 2, wherein the therapeutic agent or pharmaceuticalcompound is a thrombolytic agent, a fibrinolytic enzyme, a thrombininhibitor, an antiplatelet agent, an anticoagulant, an anti-restenoticagent, or an anti-cancer agent.
 4. The method of claim 1, wherein thebody region is a vessel, graft, or duct.
 5. The method of claim 4,wherein the body region comprises an occlusion located therein.
 6. Themethod of claim 1, wherein the body region is a gland, an organ, or atumor located in the body region.
 7. The method of claim 1, wherein thecomposition delivery element is a balloon, a stent, microbubbles, ribs,or a catheter.
 8. The method of claim 7, wherein the balloon, ribs, orthe catheter is expandable.
 9. The method of claim 7, wherein thecomposition delivery element has a surface coated or imbedded with thecomposition.
 10. The method of claim 7, wherein the composition deliveryelement is microbubbles filled with the composition.
 11. The method ofclaim 1, wherein the delivery condition is one of cavitation, microjets,shockwaves, electrical stimulation, or a chemical reaction.
 12. Themethod of claim 11, wherein the delivery condition is a shockwave havingan instantaneous magnitude between 0.1 MPa to 20 MPa.
 13. The method ofclaim 11, wherein the delivery condition is at least one region ofcavitation bubbles having a diameter of between 1 μm and 10 mm.
 14. Themethod of claim 1, wherein the delivering the radiofrequency energyprovides for prolonged delivery and imbedding of the composition withinthe body region.
 15. The method of claim 1 further comprising:determining one or more impedance measurements based on the delivery ofthe radiofrequency energy; and optimizing the delivery of theradiofrequency based on the one or more impedance measurements.
 16. Themethod of claim 1, wherein the first electrode and the second electrodehave a dielectric barrier to implement low-intensity plasma discharge.17. The method of claim 1, wherein the modulated pulses have a pulsewidth between about 0.05 to about 500 microseconds.
 18. The method ofclaim 1, wherein the modulated pulses have a pulse width between about500 microseconds and 1 second.
 19. The method of claim 1, wherein themodulated pulses have a pulse width less than 0.05 microseconds.
 20. Themethod of claim 1, wherein the modulated pulses of radiofrequency energyare gated using an ECG or another waveform signal obtained from thebody.
 21. The method of claim 1, wherein the modulated pulses aregrouped into bursts having a burst width between 100 ms to 1 s and aninterval between each burst between 1 ms to 100 ms.
 22. The method ofclaim 1, wherein the radiofrequency energy voltage is between 400V to4000V.
 23. The method of claim 1, wherein the radiofrequency energyvoltage is less than 400V.
 24. The method of claim 1, wherein theincident intensity of the radiofrequency energy is between about 0.1 to5 Joules per square millimeter.
 25. The method of claim 1 furthercomprising delivering the radiofrequency energy until an electricallimit is met.
 26. The method of claim 25, wherein the electrical limitis less than 100 Ohms.
 27. The method of claim 1, wherein the deliveryof the radiofrequency energy provides a mechanical force to enhancediffusion of the composition into the body region to enhance delivery ofthe composition.
 28. The method of claim 1, wherein the delivery of theradiofrequency energy causes vasodilation, increased cell permeability,or reversible electroporation to enhance the delivery of thecomposition.
 29. The method of claim 1, wherein the composition isdelivered to the body region prior to the delivery of the radiofrequencyenergy.
 30. The method of claim 1, wherein the first electrode and thesecond electrode are delivered on a single longitudinal member.
 31. Themethod of claim 30, wherein the single longitudinal member is a catheteror a guidewire.
 32. The method of claim 1, wherein the first electrodeis delivered on a first longitudinal member and the second electrode isdelivered on a second longitudinal member.
 33. The method of claim 32,wherein the first longitudinal member and the second longitudinal memberare independent, non-overlapping guidewires or catheters.
 34. The methodof claim 32, wherein the delivering comprises delivering the firstlongitudinal member and the second longitudinal member to the bodyregion in the same direction.
 35. The method of claim 32, wherein thedelivering comprises delivering the first longitudinal member and thesecond longitudinal member to the body region from opposite directions.36. The method of claim 1, wherein one of the first electrode or thesecond electrode is located on a patch placed outside the body region.37. The method of claim 1, further comprising: providing a thirdelectrode located on a patch placed outside the body region, whereinthird electrode is electrically coupled to the first electrode and thesecond electrode.
 38. A device for enhanced delivery of a composition toa body region of a patient utilizing radiofrequency energy, the devicecomprising: a first longitudinal member with a proximal end and a distalend with at least one lumen extending between the proximal end and thedistal end; a composition delivery element located at the distal end ofthe longitudinal member, the composition delivery element having thecomposition located on an outside surface thereof; and at least twoelectrodes coupled to a radiofrequency source and located within thecomposition delivery element, wherein the at least two electrodes arecapable of generating an electric field to enhance delivery of thecomposition to the body region.
 39. The device of claim 38, wherein thecomposition delivery element comprises a balloon.
 40. The device ofclaim 39, wherein the balloon has a porous surface.
 41. The device ofclaim 38, wherein the composition delivery element further comprises oneor more raised elements configured to score the body region.
 42. Thedevice of claim 41, wherein the raised elements are longitudinal orcircumferential elements.
 43. The device of claim 41, wherein the raisedelements have a circular cross section.
 44. The device of claim 41,wherein the raised elements have a triangular cross section.
 45. Thedevice of claim 41, wherein the raised elements are constructed of ametal or a polymer.
 46. The device of claim 41, wherein the compositionis located on the raised elements.
 47. The device of claim 38, whereinthe composition delivery element comprises expandable ribs.
 48. Thedevice of claim 38, wherein the at least two electrodes are located on asecond longitudinal member and a third longitudinal member,respectively, wherein the second longitudinal member and the thirdlongitudinal member are configured to be inserted into the lumen of thefirst longitudinal member.
 49. The device of claim 48, wherein thesecond longitudinal member and the third longitudinal member areguidewires.
 50. The device of claim 49, wherein the second longitudinalmember is configured to be located within the third longitudinal member.51. The device of claim 38, wherein the at least two electrodes arelocated on a second longitudinal member configured to be inserted intothe lumen of the first longitudinal member.
 52. The device of claim 38,wherein the at least two electrodes are balloon markers.
 53. The deviceof claim 38, wherein the at least two electrodes are insulated in amanner capable of withstanding the generation of a plasma dischargearound the at least two electrodes.
 54. The device of claim 38, whereinthe at least two electrodes are at least partially wound around thefirst longitudinal member.
 55. The device of claim 38, wherein thecomposition is a therapeutic agent or a pharmaceutical compound.
 56. Thedevice of claim 53, wherein the therapeutic agent or pharmaceuticalcompound is a thrombolytic agent, a fibrinolytic enzyme, a thrombininhibitor, an antiplatelet agent, an anticoagulant, an anti-restenoticagent, or an anti-cancer agent.